Sparsomycin derivatives

ABSTRACT

Sparsomycin derivatives of the formula ##STR1## wherein X and Y are each independently an oxo or an imino group; n is 0 or the integer 1 or 2; R 1  is a hydrogen or 1 to 4 carbon alkyl group; R 2  is a hydrogen, a 1 to 4 carbon alkyl, a 2 to 5 carbon acyl or a benzoyl group; and R is a 1 to 6 carbon alkyl, 3 to 8 carbon alkenyl, cyanomethyl carboxymethyl, carbalkoxymethyl wherein the alkoxy moiety is a 1 to 4 carbon alkoxy group, nitromethyl, alkylcarbonylmethyl wherein the alkyl moiety is a 1 to 4 carbon alkyl group, pyridyl, furanyl, or furfuryl group or a phenyl or benzyl group optionally substituted by a methylenedioxy or one to two halogen, 1 to 4 carbon alkyl, 1 to 4 carbon alkoxy, 1 to 4 carbon alkylthio, hydroxy, nitro or cyano groups or a pharmaceutically acceptable acid addition salt thereof. Also described are their use as antiprotozoals and antibacterials.

FIELD OF THE INVENTION

This invention relates to certain Sparsomycin derivatives as well astheir use as antibacterials and antiprotozoals, in particularantitrypanosomals

DESCRIPTION OF THE PRIOR ART

The Sparsomycin derivatives of this invention are known in the priorart, see R. J. Ash et al. Antimicrobial Agents and Chemotherapy, April1984 p. 443-445 and G. A. Flynn and R. J. Ash, Biochemical andBiophysical Research Communications, vol. 114, No. 1, 1983, July 18,1983 p. 1-7.

SUMMARY OF THE INVENTION

This invention relates to pharmaceutically active Sparsomycinderivatives of general Formula I ##STR2## wherein X and Y are eachindependently an oxo or an imino group; n is O or the integer 1 or 2; R₁is a hydrogen or 1 to 4 carbon alkyl group; R₂ is a hydrogen, a 1 to 4carbon alkyl, a 2 to 5 carbon acyl or a benzoyl group; and R is a 1 to 6carbon alkyl, 3 to 8 carbon alkenyl, cyanomethyl, carboxymethyl,carbalkoxymethyl wherein the alkoxy moiety is a 1 to 4 carbon alkoxygroup, nitromethyl, alkylcarbonylmethyl wherein the alkyl moiety is a 1to 4 carbon alkyl group, pyridyl, furanyl, or furfuryl group or a phenylor benzyl group optionally substituted by a methylenedioxy or one to twohalogen, 1 to 4 carbon alkyl, 1 to 4 carbon alkoxy, 1 to 4 carbonalkylthio, hydroxy, nitro or cyano groups or a pharmaceuticallyacceptable acid addition salt thereof. This invention further relates tothe use of these Sparsomycin derivatives as antibacterial andantiprotozoal agents.

As used herein, the phrase a 1 to 4 carbon alkyl group includes straightand branched chain alkyl groups such as methyl, ethyl, isopropyl andisobutyl.

As used herein, the phrase a 1 to 6 carbon alkyl group includes straightand branched chain alkyl groups such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, pentyl, isopentyl, and n-hexyl.

As used herein, the phrase a 1 to 4 carbon atom alkoxy group includesstraight and branched chain alkoxy groups such as methoxy, ethoxy,isopropoxy and tertbutoxy.

As used herein, the phrase 1 to 4 carbon atom alkylthio group includesstraight and branched chain alkylthio groups such as methylthio,ethylthio, n-butylthio and isobutylthio.

As used herein, the phrase a 2 to 5 carbon atom acyl group includesstraight and branched chain acyl groups such as acetyl, propanoyl,butanoyl and isopentanoyl.

As used herein, the phrase a 3 to 8 carbon alkenyl group includesstraight and branched chain alkenyl groups wherein the carbon atom atthe point of attachment is not an unsaturated carbon atom and includes2-butenyl, 2-propenyl, 2-methyl-3-ethyl-2-pentenyl, 5-methyl-2-hexenyland 3-butenyl.

As used herein, the term halogen includes fluoro, chloro, bromo and iodogroups.

As used herein, a cyanomethyl group is taken to mean a group of theformula --CH₂ CN.

As used herein a carboxymethyl group is taken to mean a group of theformula --CH₂ CO₂ H.

As used herein, a carbalkoxymethyl group is taken to mean a group of thestructure ##STR3## wherein the alkoxy moiety is a 1 to 4 carbon alkoxygroup.

As used herein, a nitromethyl group is a group of the formula --CH₂ NO₂.

As used herein, an alkylcarbonylmethyl group is a group of the structure##STR4## wherein the alkyl moiety is a 1 to 4 carbon alkyl group.

The preferred compounds of this invention are those compounds of FormulaI wherein R is a furfuryl or furanyl group or an optionally substitutedphenyl or benzyl group. Other preferred compounds are those compounds ofFormula I wherein R₁ is a methyl group and R₂ is a hydrogen group. Yetother preferred compounds are those compounds of Formula I wherein X andY are oxo groups. Finally, the preferred compounds of this inventioninclude those compounds of Formula I wherein R is a 3 to 8 carbonalkenyl group.

The more preferred compounds of this invention are those compounds ofFormula I wherein R is a phenyl or benzyl group optionally substitutedat the para position. Also included in the more preferred group ofcompounds of this invention are those compounds of formula I wherein nis the integer 1.

Especially preferred are those Formula I compounds wherein R is apyridyl, furanyl or furfuryl group or an optionally substituted phenylor benzyl group and n is the integer 1 wherein the absoluteconfiguration of the carbon atom bearing the CH₂ OR₂ group is S andwherein the absolute configuration at the sulfur atom is R. Alsopreferred are those Formula I compounds wherein R is other than apyridyl, furanyl or furfuryl group or an optionally substituted phenylor benzyl group which possess the same relative configuration at thesulfur atom, but which may be designated as R or S depending upon theexact nature of the sulfur atom substituents.

The pharmaceutically acceptable acid addition salts of the compounds ofFormula (1) above include the nontoxic, carboxylic acid salts formedwith any suitable inorganic or organic bases. Illustratively, thesesalts include those of alkali metals, as for example, sodium andpotassium; alkaline earth metals, such as calcium and magnesium; lightmetals of Group IIIA including aluminum; and organic primary, secondaryand tertiary amines, as for example, trialkylamines, includingtriethylamine, procaine, dibenzylamine, 1-ethenamine,N,N'-dibenzylethylenediamine, dihydroabietylamine,N-(lower)alkylpiperidine, and additional amines which have been used toform non-toxic salts with benzylpenicillin. These salts can be preparedusing conventional means such as contacting and neutralizing a solutionof the caraboxylic acid in a polar solvent with a stoichiometricquantity of base. In general, the pharmaceutically acceptable salts arecrystalline materials which are more soluble in water and varioushydrophilic solvents and which in comparison to their free acid formsgenerally demonstrate higher melting points and an increased chemicalstability.

The compounds of this invention can be prepared in any suitable mannerby analogous procedures readily known to those skilled in the art. Inparticular, applicants have prepared the Structure I compounds utilizingone of several synthetic pathways. Although most of the Structure Icompounds can be prepared by any of the pathways, due to potential sidereactions and unavailability of reactants, one pathway may be preferredover the other for a given desired product as will be readily apparentto the ordinary artisan.

In method A a salt of Structure II is first treated with a base such astriethylamine to yield the corresponding free base. ##STR5## wherein Ris as defined above in Structure I and X is an anion, typically chlorideion.

Subsequently, the free amine is coupled with a uracylacrylic acid ofStructure III ##STR6## wherein X, Y and R₁ are as defined above. Finallybase hydrolysis of the benzoyl ester with, for example lithiumhydroxide, yields a Structure I compound wherein n is the integer 1 andR₂ is a hydrogen group.

In method B a hydroxymethyl compound of Structure IV ##STR7## wherein Ris as defined above is coupled with a uracylacrylic acid of StructureIII to yield a sparsomycin derivative of Structure I wherein R₂ is ahydrogen group and n is zero.

In method C an amino ester of Structure V wherein R is as defined aboveand R¹ is a 1 to 4 carbon alkyl group is coupled with a Structure IIIuracylacrylic acid. ##STR8## Reduction of the ester group in theresulting coupled product yields a Structure I sparsomycin derivativewherein R₂ is a hydrogen group and n is zero.

This ester reduction can be accomplished in any manner generally knownin the art which will not affect the other functionalities of thecompound. Suitable means of reducing the ester group include metalhydride reductions such as by using lithium aluminum hydride or sodiumor lithium borohydride; catalytic reductions employing hydrogen gas anda matallic catalyst such as Raney nickel, platinum, palladium, rhodium,ruthenium and platinum oxide; and dissolving metal reductions employinglithium, sodium, potassium, calcium, zinc, magnesium, tin or iron inliquid ammonia or a low-molecular weight aliphatic amine or sodium,aluminum or zinc amalgam, zinc, tin or iron in a hydroxylic solvent orin the presence of an aqueous mineral or organic acid such as formic,acetic or hydrochloric acid.

As is apparent, the coupling reactions in methods A, B and C are simpleamidation reactions and are facilitated by the various reagents known tothose skilled in the art such as dicyclohexylcarbodiimide (DCC),N,N'-carbonylodiimidazole,N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) anddiethylcyanophosphonate. Applicants have employed DCC in these couplingreactions preferably in conjunction with a compound such ashydroxybenzotriazole (HOBT) or N-hydroxysuccinimide which is known toincrease yields and decrease racemization in DCC facilitated peptidecouplings. The couplings are performed by reacting approximatelyequimolar amounts of an appropriate amine of Structure II, IV or V witha uracylacrylic acid of Structure III for about 1 to 4 days depending onthe reactants, the solvent and the temperature which can be from -20° C.to 60° C. preferably about 0° C. to 25° C. or room temperature. Asuitable solvent is any non-reactive solvent in which the reactants andcoupled sparsomycin product are soluble. Because the solubility of thecoupled products is exceedingly low in most organic solvents, the use ofdimethylformamide (DMF) is preferred.

The Structure II salt of method A is prepared by acid hydrolysis of anoxazoline sulfoxide of Structure VI ##STR9## wherein R is as definedabove. This hydrolysis is typically performed by allowing the sulfoxideto react in a solution of dilute hydrochloric acid at room temperature.The Structure VI sulfoxide is prepared from the corresponding sulfide bywell known oxidation procedures such as by treatment withmeta-chloro-peroxybenzoic acid (MCPBA) or 30% hydrogen peroxidesolution. The sulfide is in turn prepared by the reaction of a thiol,RSH wherein R is as defined above, with 2-pheny-4-hydroxymethyloxazolineor preferably a more reactive derivative of the hydroxymethyloxazolinesuch as its mesylate.

The hydroxymethyl compounds of Structure IV used in method B areprepared by reduction of the corresponding carboxylic acid. Thisreduction is typically performed by use of lithium aluminum hydride,diborane or sodium borohydride and a Lewis acid catalyst such asaluminum chloride or boron trifluoride. This carboxylic acid is preparedby reaction, preferably a base catalyzed reaction, of cysteine,preferably D-Cysteine, and the compound RX wherein R is as defined aboveand X is a chloro, bromo, iodo or any other good leaving group. Asshould be apparent, the R group must be a saturated carbon atom and willpreferably be a primary carbon atom in order to facilitate thenucleophic displacement. Certain Structure I R groups are unable toundergo this requisite nucleophilic reaction, i.e., RX+Cysteine, andaccordingly Structure I compounds wherein R is phenyl, furanyl, orpyridyl cannot be prepared by method B.

The Structure V amino esters of method C can be prepared from thecorresponding t-butyloxycarbonyl (BOC) amine derivatives by mild acidhydrolysis. These BOC derivatives can be prepared by reaction,preferably a base catalyzed reaction of a sulfide, RSH wherein R is asdefined above, with an acrylic acid of Structure VII ##STR10## whereinR' is a 1 to 4 carbon alkyl group. Alternatively where a Structure Icompound wherein R is furanyl is desired, 2,5-dimethoxy-2,5-dihydrofurancan be reacted with a 1 to 4 carbon alkyl ester of cysteine along withp-toluenesulfonic acid. Upon subsequent work up with a mild base such assodium bicarbonate, a Structure V amino ester wherein R is furanyl isproduced.

Moreover, as will be readily apparent to those skilled in the art, theuse of protecting groups to prevent the formation of undesired productsin the above described reactions can be desirable in many instances. Forexample, the phenol ofN-[1-(hydroxymethyl)-2-[(4-hydroxyphenyl)thio]-ethyl]-3-[6-methyluracil]-2-propenamideis preferably silated prior to treatment with NaIO₄ to oxidize the thiogroup to a sulfinyl group.

The compounds described herein are useful anti-protozoal agents inanimals. The term "animals" is intended to include inter alia mammals,such as mice, rats, guinea pigs, rabbits, ferrets, dogs, cats, cows,horses and primates including man. Also encompassed within the termanimals are both fish and fowl. The term "fowl" is intended to includemale or female birds of any kind including parrots and canaries, but isprimarily intended to encompass poultry which are commercially raisedfor eggs or meat. Accordingly, the term "fowl" is particularly intendedto encompass hens, cocks and drakes of chickens, turkeys and ducks.

The term "protozoa" is intended to include those members of the subphylaSarcomastigophora and Sprozoa of the phylum Protozoa. More particularly,the term "protozoa" as used herein is intended to include those generaof parasitic protozoa which are important to man because they eithercause disease in man or his domestic animals. These genera are for themost part found classified in the superclass of Mastigophora of thesubphylum Sarcomastigophora and the class of Telosporea of the subphylumSporozoa in the classification according to Baker (1969). Illustrativegenera of these parasitic protozoa include Histomonas, Trypanosoma,Giardia, Trichomonas, Eimeria, Isopora, Toxoplasma and Plasmodium.

Indeed, a preferred embodiment of the present invention is the use ofthese compounds as antiprotozoal agents in the treatment of intestinalcoccidia in commercial poultry. The economic importance of intestinalcoccidia is highly significant. Thus in 1972, the estimated loss to thepoultry industry in the United States due to coccidial infections wasapproximately 47 million dollars. Due to the rapid development of drugresistance by coccidia, and due to the relatively high toxicity of someof the drugs used in the treatment of coccidiosis, there is a need foreffective coccidiostats that are non-toxic and to which intestinalcoccidia do not develop rapid drug resistance.

Furthermore, the products of the present invention are antibacterialagents, having activity against Grampositive and Gram-negative bacteriasuch as Staph. aureus, E. coli, Klebsiella pneumoniae, Strep. faecalis,and Strep. pyogenes.

The compounds described herein are employed in amounts that areeffective against bacteria and protozoa. These amounts will depend, ofcourse, upon various factors, such as the type and nature of theprotozoal or bacterial infection, the activity of the specific compound,the age, sex and species of animal treated and whether the treatment isprophylactic or therapeutic. In general the compounds described hereincan be orally or parenterally administered, preferably parenterally at adaily dose ranging from 0.1 to 100 mg/kg of patient body weight,preferably from about 1 to 50 mg/kg.

Due to the low toxicity of the compounds described herein, the compoundscan be safely administered ad libitum via the drinking water of the testanimals in the treatment of coccidiosis in fowl. Generally speaking,concentrations of the active ingredient ranging from about 0.1% to about2% are suitable, depending primarily upon the nature of the protozoalinfection to be treated whether prophylactic or therapeutic, theseverity of the infection and the period of treatment.

For oral administration the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, powders,solutions, suspensions or emulsions. The solid unit dosage forms can bea capsule which can be of the ordinary gelatin type containing, forexample, lubricants and inert filler, such as lactose, sucrose andcornstarch. In another embodiment the compounds of general Formula I canbe tableted with conventional tablet bases such as lactose, sucrose andcornstarch in combination with binders, such as acacia, cornstarch orgelatin, disintegrating agents such as potato starch or alginic acid,and a lubricant such as stearic acid or magnesium stearate.

For parenteral administration the compounds may be administered asinjectable dosages of a solution or suspension of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid such as water and oils with or without theaddition of a surfactant and other pharmaceutically acceptableadjuvants. Illustrative of oils which can be employed in thesepreparations are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil and mineral oil. Ingeneral, water, saline, aqueous dextrose and related sugar solutions,ethanol and glycols such as propylene glycol or polyethylene glycol arepreferred liquid carriers, particularly for injectable solutions.

The compounds can be administered in the form of a depot injection orimplant preparation which may be formulated in such a manner as topermit a sustained release of the active ingredient. The activeingredient can be compressed into pellets or small cylinders andimplanted subcutaneously or intramuscularly as depot injections orimplants. Implants may employ inert materials such as biodegradablepolymers or synthetic silicones, for example, Silastic, silicone rubbermanufactured by the Dow-Corning Corporation.

The following examples illustrate the preparation of the Structure Iderivatives.

EXAMPLE 1 4-[[2-phenyl-(2-oxazolin-4-yl)]methylthio]phenol

To a solution of 11.1 g (67mm) of 2-phenyl-2-oxazolin-4-yl methylalcohol in 150 ml methylene chloride was added 5.25 ml (67 mm) ofmesylchloride at 0° C. To this stirred solution under argon was added9.4 ml (67 mm) of triethylamine over a 30 minute period. The methylenechloride was removed in vacuo. The residue was diluted with 10 ml DMFand pumped on at high vacuum. 8.5 ml (67 mm) of 4-mercaptophenol in 5 mlof DMF was added followed by 9.4 ml (67 mm) of triethyamine. Afterstirring for 1 day, 0.5 g sodium borohydride was added. After a total of3 days another 0.5 of sodium borohydride was added followed by a onehour delay. The reaction mixture was poured into 300 ml ethylacetate andwashed with 3×150 ml of water, 150 ml 0.1 N, HCl, and brine, then driedover Na₂ SO₄ and concentrated to a yellow oil. Dilution with 50 ml ethylacetate and seeding gave 4.23 g of a white crystalline solid isolated byfiltration mp. 114.5°-165.5° C.

EXAMPLE 2 4-[[2-Phenyl-(2-oxazolin-4-yl)]methylsulfinyl]phenol

To a solution of 2.85 q (10.0 mm) of the sulfide prepared in Example 1in 50 ml methylenechloride at 25° C. was added 2.1 g (12 mm) of 90%MCPBA. Small portions of MCPBA were added until conversion was completedas indicated by thin layer chromatography. The soution was poured into50 ml methylenechloride, washed with 100 ml NaHCO₃ solution, dried overNa₂ SO₄, filtered and concentrated to give crude title compound.

EXAMPLE 3 5-benzylcysteine hydrochloride

31.5 g (200 mmole) of cysteine was dissolved in 750 ml degassed absoluteethanol. 84 ml (600 mmole) of triethylamine was added followed by 24 mlbenzylbromide and the mixture was stirred at 25° C. for 18 hours. Themixture was poured into 3 l of water. The resulting transparent solutionwas stirred while 200 ml lN HCl was added. Upon cooling, the crystalswere filtered and suction dried to give 26.0 g (123 mmole), 62%, of awhite solid, the title compound.

EXAMPLE 4 2-amino-3-benzylthio propan-1-ol

To a stirred slurry of 10.0 g of lithium aluminum hydride in 500 ml dryTHF under argon was added 26.0 g (123 mmol) of 5-benzylcysteinehydrochloride carefully over a 30 minute period with cooling. The slurrywas then brought to reflux for 18 hours. Upon cooling, 10.0 ml of water,10.0 ml 15% NaOH solution and 30.0 ml of water were carefully added.Filtration, washing with ethylacetate and concentration of the filtrategave 19.9 g of the title compound as a viscous oil.

EXAMPLE 5 Methyl2-amino-3-[(4-hydroxyphenyl)thio]propanoatehydrochloride

20 g (100 mmol; 120 ml) methyl 2-(butoxycarbonylamino)-propenoate inchloroform was dissolved in 180 ml of methanol. 13.88 g (110 mmol)4-mercaptophenol was added and the mixture was then stirred at roomtemperature under nitrogen for 24 hours. Solvents were removed in vacuountil foaming occurred, then the mixture was taken up in 700 ml dryether. HCl gas was bubbled through the solution, quickly forming a whiteprecipitate. Bubbling was continued for 1 hour with cooling, then thesolution was cooled to 5° C. and filtered to yield the title compound in80.8% yield.

EXAMPLE 6 Ethyl 2-Amino-3-(2-furanylthio)propanoate

To 16.25 g (125 mmol) of 2,5-dimethoxy-2,5-dihydrofuran and 23.20 g (125mmol) of ethyl 2-amino-3-mercaptopropanoate in 100 ml dry acetonitrilewas added approximately 0.15 g of tosyl chloride. The mixture wasstirred 1 hour at room temperature under nitrogen during which timecomplete solution was attained which became very dark. The mixture wasconcentrated in vacuo, taken up in ethyl acetate, then extracted withaqueous NaHCO₃ solution followed by saturated NaCl solution. The organicportion was dried over MgSO₄, filtered then concentrated to 50 ml. Theconcentrate was then chromotographed to give 8.35 g (31.0%) of the titlecompound as a dark oil.

EXAMPLE 7N-[1-Carbomethoxy-2-[(4-hydroxyphenyl)thio]ethyl]-3-(6-methyluracil)-2-propenamide.

730 mg (3.15 mmol) of amino ester from Example 5 in 5 ml of dry DMF wastreated with 0.24 ml (3.15 mmol) triethylamine. The resultingprecipitate was filtered and 0.61 g (3.15 mmol) 6-methyluracylacrylicacid along with 0.47 g (3.47 mmol) HOBT was added. The flask was warmedslightly to make the mixture more homogeneous, then cooled to ˜-15° C.before adding 0.65 g (3.15 mmol) of DCC. The mixture was stirred 24hours at room temperature. Ethanol was added and the mixture filtered.DMF was removed via kugelrohr at 70° C. The remaining solid was taken upin ethanol and filtered. The filtrate was concentrated in vacuo thendiluted with ethanol, cooled to -15° C. then filtered. All portions werecombined, concentrated then chromatographed on silica to give the titlecompound.

EXAMPLE 8N-[1-(hydroxymethyl)-2-(benzylthio)ethyl]-3-(6-methyluracil)-2-propenamide

9.9 g (50 mmol) of the amine from example 4 and 10.0 g (50 mmol) of6-methyluracylacrylic acid were dissolved in 125 ml degassed DMF. Thestirred solution was cooled to 0° C. and 9.0 g of 1-hydroxybenztriazoleand 11.5 g of DCC were added (56 mmol). The reaction was allowed toproceed for 3 days at room temperature, then filtered and was washedwith ethylacetate. The combined filtrate was diluted with lLethylacetate, washed with dilute HCl, saturated NaHCO₃ solution, andthen brine. Drying over Na₂ SO₄ and concentration in vacuo gave 10.6 gof the title compound as a tan solid.

EXAMPLE 9 4-[(3-benzoyloxy-2-aminopropyl)sulfinyl]phenol hydrochloride

1.3 g (4.3 mM) of the oxazoline from Example 2 was dissolved in 30 mLethanol and treated with 8 mL lN HCl for 3 hours. The solvents wereremoved under reduced pressure and the resulting foam was dried underhigh vacuum for 18 hours at 50° C. to give the title compound.

EXAMPLE 10N-[1-(Benzoyloxymethyl)-2-[[4-(hydroxy)phenyl]sulfinyl]-ethyl]-3-(6-methyluracil)-2-propanamide

The HCl salt from Example 9 was dissolved in 15 ml of dry DMF andtreated at 25° C. with 900 mg (4.5 mm) of 6-methyluracilacrylic acid,1.0 g of HOBT, 600 μL (0.43 mm) of triethylamine and 1.2 g of DCC. Theresulting mixture was stirred for 3 days, then treated with 10 drops ofH₂ O, stirred for 1 hour, filtered, and the DMF was removed under highvacuum (50° C. at 0.1 mm). The residue was taken up in dimethylsulfoxideand chromatographed on silica gel to give the title compound as a tansolid.

EXAMPLE 11N-[1-(Hydroxymethyl)-2-[[4-(hydroxy)phenyl]sulfinyl]-ethyl]-3-(6-methyluracil)-2-propenamide

To a mixture of 1500 mg (3.0 μM) of benzoate from Example 10 in 30 ml ofethanol at 25° C. was added 15 ml of lN LiOH. After 1 hour, 2.5 ml of 6NHCl was added and the solvents were removed in vacuo. The solid wasdissolved in 5 ml of H₂ O and 10 ml of ethanol, then heated and allowedto cool. The solid was filtered, washed with H₂ O, and dried under highvacuum to give 640 mg of the title compound as an off white powder.

EXAMPLE 12N-[1-(Hydroxymethyl)-2-[(phenylmethyl)sulfinyl]ethyl]-3-(6-methyluracil)-2-propenamide

4.7 g (11.6 mmol) of sulfide from Example 8 was dissolved in 90 ml ofdioxane and 45 ml of H₂ O, then treated with 3.0 g (14.0 mmol) ofpowdered NaIO₄. After stirring at 25° C. for 18 hours, the mixture wasdiluted with 250 ml of isopropanol and filtered. The filtrate wasconcentrated to an oily residue, which upon chromatography yielded thetitle compound.

EXAMPLE 13N-[1-(Hydroxymethyl)-2-[[4-(hydroxy)phenyl]sulfinyl]-ethyl]-3-[6-(methyl)uracil]-2-propenamide

2.0 g (4.94 mmol) of the sulfide from Example 7 and 0.84 g (12.4 mmol)of imidazole were dissolved in 25 ml DMF. 1.11 g (7.41 mmol) oft-butyldimethylsilylchloride was then added and the mixture stirred 20hours at room temperature. The mixture was filtered and DMF removed viarotary evaporation at high vacuum. The residue was taken up in 10 ml of20% MeOH/EtOAC and chromatographed using 0 →10% MeOH/EtOAC to give the0- silated product.

To 0.145 g (6.58 mmol) of LiBH₄ in 30 ml dry DMF was added 1.14 g (2.19mmol) of the silyl derivative. 0.0228 g (0.22 mmol) of trimethoxyboranewas then added and the mixture stirred at room temperature for 20 hours.100 mg (4.55 mmol) of LiBH₄ was then added and the mixture stirred anadditional 44 hours. Subsequently, 20 ml of H₂ O was added followed bylN HCl added until the light yellow reaction mixture became colorless.The solution was poured into 100 ml of ethyl acetate and any remainingprecipatate was dissolved in lN HCl and poured into the ethylacetatesolution. The aqueous portions were extracted 3 times with 100 ml ofethyl acetate, then washed with brine followed by drying over MgSO₄. Themixture was filtered followed by concentration to dryness in vacuo togive 1.02 g (94.7% of the hydroxymethyl-0-silylated sulfide product at awhite powder.

1.00 g (2.03 mmol) of this sulfide was dissolved in 50 ml of methanol,then 25 ml of H₂ O and 0.435 g (2.03 mmol) of NaIO₄ was added. Thismixture was stirred at room temperature for 16 hours then poured into 50ml of isopropanol and filtered to give a solid product. Upon subsequentchromatography the 0-silated sulfinyl derivative was isolated in 49%yield.

Finally 28 mg of this white powder was treated in refluxing acetonitrilewith excess CsF. Solvent was removed in vacuo and the materialchromatographed on silica using 5% H₂ O/ acetone to give the titlecompound in 79% yield.

We claim:
 1. A method of inhibiting the growth of protozoa in animals in need thereof which comprises administering an antiprotozoal amount of a compound of the formula ##STR11## wherein X and Y are each independently an oxo or an imino group; n is 0 or the integer 1 or 2; R₁ is a hydrogen or a 1 to 4 carbon alkyl group; R₂ is a hydrogen, a 1 to 4 carbon alkyl, a 2 to 5 carbon acyl or a benzoyl group; and R is a 1 to 6 carbon alkyl, 3 to 8 carbon alkenyl, pyridyl, furanyl or furfuryl group; or R is a phenyl or benzyl group each optionally substituted by a methylenedioxy group or one or two halogen, 1 to 4 carbon alkyl, 1 to 4 carbon alkoxy, 1 to 4 carbon alkylthio, hydroxy, nitro or cyano groups, or a pharmaceutically acceptable acid addition salt thereof.
 2. A method of claim 1 wherein X and Y are each an oxo group.
 3. A method of claim 2 wherein R is a phenyl or benzyl group each optionally substituted by a methylenedioxy group or one or two halogen, 1 to 4 carbon alkyl, 1 to 4 carbon alkoxy, 1 to 4 carbon alkylthio, hydroxy, nitro or cyano groups.
 4. A method of claim 3 wherein the phenyl or benzyl group is substituted at the para position.
 5. A method of claim 3 wherein R is a pyridyl, furanyl or furfuryl group.
 6. A method of claim 2 wherein R₁ is a methyl group and R₂ is a hydrogen group.
 7. A method of claim 2 wherein R is a 3 to 8 carbon alkenyl group.
 8. A method of claim 2 wherein n is the integer
 1. 